Identification of Novel Approaches for Cardioprotection against Ischemia-reperfusion Injury
Heart attack is one of the major causes of death in elderly populations worldwide. Ischemia-reperfusion (I/R) injury is significantly involved in diseases such as heart attack and stroke, and it occurs as a result of the disruption and subsequent restoration of blood supply. The reperfusion process of the ischemic tissue is essential for the survival and recovery of the tissue, but at the same time initiates secondary damage. The I/R injury differs from the primary ischemic damage and is detrimental to patient survival. The I/R injury has been identified to be a result of several mitochondrial dysfunctions during reperfusion stage, including the production of reactive oxygen species (ROS), opening of the mitochondrial permeability transition pore (mPTP), loss of membrane potential, and activation of downstream cell death signaling pathways. In clinical practice, there is a lack of effective treatment for I/R injury.
Here we report that tricarboxylic acid cycle intermediate α-ketoglutarate (α-KG), when administered at the onset of reperfusion, confers robust cardioprotection against I/R injury and reduces myocardial infarct size in vivo by ~70%. Previously, α-KG has been shown to bind to the mitochondrial F1Fo-ATP synthase/ATPase using drug affinity responsive target stability (DARTS), a small-molecule target identification method. The structure of the mPTP has been studied for decades. It was suggested that ATP synthase plays a critical role in the mPTP opening. Here we provide evidence that α-KG regulates the interaction between ATP synthase to CypD. The opening of the mPTP has been suggested to be regulated by the interaction between ATP synthase to CypD. We further showed that cardioprotection by α-KG against I/R injury is abolished by CypD deficiency. Our findings link a basic metabolite to a critical mitochondrial component and provide novel approaches for cardioprotection against IR injury.